4DO6: Pharmacological chaperones for human alpha-N-acetylgalactosaminidase

Citation:
Abstract
Schindler/Kanzaki disease is an inherited metabolic disease with no current treatment options. This neurologic disease results from a defect in the lysosomal alpha-N-acetylgalactosaminidase (alpha-NAGAL) enzyme. In this report, we show evidence that the iminosugar DGJNAc can inhibit, stabilize, and chaperone human alpha-NAGAL both in vitro and in vivo. We demonstrate that a related iminosugar DGJ (currently in phase III clinical trials for another metabolic disorder, Fabry disease) can also chaperone human alpha-NAGAL in Schindler/Kanzaki disease. The 1.4- and 1.5-A crystal structures of human alpha-NAGAL complexes reveal the different binding modes of iminosugars compared with glycosides. We show how differences in two functional groups result in >9 kcal/mol of additional binding energy and explain the molecular interactions responsible for the unexpectedly high affinity of the pharmacological chaperones. These results open two avenues for treatment of Schindler/Kanzaki disease and elucidate the atomic basis for pharmacological chaperoning in the entire family of lysosomal storage diseases.
PDB ID: 4DO6Download
MMDB ID: 103776
PDB Deposition Date: 2012/2/9
Updated in MMDB: 2012/12
Experimental Method:
x-ray diffraction
Resolution: 1.6  Å
Source Organism:
Similar Structures:
Biological Unit for 4DO6: dimeric; determined by author and by software (PISA)
Molecular Components in 4DO6
Label Count Molecule
Proteins (2 molecules)
2
Alpha-n-acetylgalactosaminidase(Gene symbol: NAGA)
Molecule annotation
Chemicals (25 molecules)
1
10
2
3
3
4
4
1
5
3
6
1
7
2
8
1
* Click molecule labels to explore molecular sequence information.

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